Microsurgical treatment for hypothalamic hamartoma in children with precocious puberty

BACKGROUND: We review the surgical treatment of hypothalamic hamartoma causing precocious puberty. METHODS: Six children (three girls and three boys) with precocious puberty secondary to hypothalamic hamartoma were recruited for our study. The mean age of the patients was 30 months old (range 13 months to 5 years), and the mean age of the onset of puberty was 7.3 months. All patients were treated by microsurgery. RESULTS: All patients had higher then normal stature, body weight, bone growth, and serum levels of sexual hormones. The boys presented with mature external genitalia, pubic hair, frequent erection, and acne, while the girls presented with growth of breasts and menarche. Magnetic resonance image (MRI) revealed an isointense mass below the tuber cinereum extending into the supersellar and interpeduncular cistern, ranging from 4 to 12 mm in diameter, consistent with pedunculate hamartoma. The hamartoma was removed completely via a right pterional approach. The symptoms and signs of precocious puberty resolved completely, and sexual hormone levels decreased to the pre-pubertal range in all six patients without any postoperative complications. CONCLUSION: We report a series of six children with hypothalamic hamartoma-induced precocious puberty who underwent microsurgical treatment. All of them recovered completely to their age-appropriate state. Microsurgery is a good choice of treatment for pedunculate hypothalamic hamartoma.     

Hypothalamic hamartoma: the role of surgery

A hypothalamic hamartoma associated with true precocious puberty in a 7-month-old girl is hereby reported. Hormonal studies disclosed elevated serum levels of luteinizing hormone (LH) and follicle stimulating hormone, both of which responded well to LH-releasing hormone stimulation. Following a subtotal removal of the tumor, the clinical manifestations of precocious puberty as well as associated endocrinological abnormalities returned to normal. The role of surgery for this lesion, which appears to be safe when a planned microsurgical course is employed, is discussed.     

Neuroendocrine mechanisms mediating awakening of the human gonadotropic axis in puberty

The hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator presides over the pulsatile and feedback-regulated activities of the pituitary-gonadal axis. Awakening of synchronous activity of the GnRH neuronal ensemble in the earliest stages of puberty heralds the onset of full activation of the reproductive axis in girls and boys. Progression from prepuberty to adulthood in boys is directed by marked (30-fold) amplitude enhancement of pulsatile luteinizing hormone (LH) secretion, as assessed by an ultrasensitive immunofluorometric assay and deconvolution analysis. There is a much less apparent rise in LH secretory burst frequency (approximately 1.3-fold increase). Consequently, human puberty is an amplitudedriven neuroendocrine maturational process. However, less is known about pulsatile follicle-stimulating hormone (FSH) release in puberty. Multiple pathophysiologies that result in hypogonadotropic hypogonadism can converge on a final common mechanism of attenuated hypothalamic GnRH pulse generator output and hence reduced LH (and FSH) secretion. Disturbances may take the form of reduced GnRH pulse frequency and/or attenuated GnRH secretory burst mass. When the pathophysiology of hypogonadism originates exclusively in a failed GnRH pulse generator, then either treatment of the primary disease process where possible (e.g., by refeeding in starvation, improved metabolic control in diabetes mellitus, dopamine agonist treatment in hyperprolactinemia, etc.) and/or treatment with pulsatile GnRH (e.g., in Kallmann's syndrome, isolated hypothalamic lesions, etc.) can provide relevant therapeutic options in children and adults.     

Suprasellar arachnoid cyst associated with precocious puberty: report of an operated case and review of the literature]

The pathogenesis remains unknown in the majority of patients with precocious puberty, and yet infrequently such causative cerebral lesions as hypothalamic hamartomas are associated with sexual precocity. We reported a rare case of suprasellar arachnoid cyst in an infant presenting with precocious puberty, which eventually disappeared after a cyst-peritoneal shunt. It was believed that the mass effect of the arachnoid cyst upon the hypothalamus was, at least in part, responsible for development of precocious puberty. The role of surgical decompression of the cyst was also discussed. A one-year-old girl was admitted to the hospital for evaluation of genital bleeding which had persisted on and off for two months. The height, 80cm, and the weight, 12.4kg, exceeded by far the two standard deviations from the mean level of the normal population. In addition she had the development of breast tissue as classified Tanner's Stage II, and both pubic and axillary hair. The bone age by skeletal survey of the hand was rated as 3 years. Endocrinological examination showed that serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol had increased for her age, to levels equivalent to those for females at puberty. An LH-RH test revealed an excessive LH reaction. There were no definite neurological deficits. CT and MRI demonstrated the presence of a large arachnoid cyst involving the suprasellar region as well as the right middle and posterior fossa. After the patient underwent a cyst-peritoneal shunt, the cyst decreased in size and such symptoms as genital bleeding and breast growth disappeared. Serum levels of her LH and FSH also significantly decreased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypothalamic hamartoma with precocious puberty--a case report

A case of hypothalamic hamartoma with precocious puberty is presented and the literature of reported cases is reviewed. An 8-year-old boy was admitted to our hospital because of precocious puberty and mental retardation. His genital development was Tanner's stage 4 and pubic hair was Tanner's stage 3. Bone age was 11 years. Plain CT showed an isodense mass in the suprasellar cistern which was not enhanced following contrast administration. Metrizamide CT cisternography showed a filling defect in the suprasellar cistern. Endocrinological evaluation revealed high levels of serum luteinizing hormone (LH) and testosterone with a marked response of LH to LH-RH injection. A left frontotemporal craniotomy was performed and the tumor was partially removed. The tumor was gray, firm and well-circumscribed with poor vascularity. Postoperatively, a right oculomotor palsy and transient diabetes insipidus developed. He was discharged ambulatory one month later. Serum LH and testosterone returned to normal and the response of LH to LH-RH injection became normal. Hamartoma was diagnosed on histological examination. Electron micrographic study showed numerous dense granules with approximately 0.1 mu in diameter, in which Judge proved LH-RH by immunofluorescent study in 1977. Our case supports the hypothesis that hypothalamic hamartoma may cause precocious puberty by autonomous secretion of LH-RH and we consider that neurosurgical treatment is recommended.     

Role of metastin in the release of gonadotropin-releasing hormone from the hypothalamus of the male rat

Recent genetic analysis has suggested that the expression of the orphan receptor GPR54 is essential for the onset of puberty in both rodents and humans. Indirect evidence has suggested that this action is via gonadotropin-releasing hormone induction of luteinizing hormone release. The experiments described here were intended to provide direct evidence that metastin, the naturally occurring ligand for GPR54, was capable of stimulating GnRH secretion by examining GnRH release from an immortalized hypothalamic cell line (GT1-7) and from male rat hypothalamic explants. GT1-7 cells were treated for 2(1/2) hours and overnight with the biologically active fragment of metastin, metastin(45-54), in amounts ranging from 0.1 nM to 1 muM. Hypothalamic fragments were obtained from infantile male rats and exposed to progressively increasing concentrations of metastin(45-54) (0.1 nM to 1 muM) for 1-hour periods. In both experiments, GnRH release was measured by radioimmunoassay (RIA). The release of metastin from hypothalami obtained from infantile and adult male rats was also determined. Explants were incubated for 6 hours, and the release of metastin into the media was determined by RIA. The results support the hypothesis that metastin stimulates GnRH secretion from the hypothalamus. The data indicate that an increase in the secretion of metastin, rather than the appearance of the receptor, is required for puberty onset. The results also suggest that metastin influences the GnRH-secreting neurons indirectly via an interneuron rather than acting directly on the GnRH-secreting neurons.     

促性腺激素释放激素类似物在妇科的应用研究进展

促性腺激素释放激素(GnRH)由下丘脑分泌,刺激或抑制垂体促性腺激素的分泌,有相当的活性潜能。在治疗妇科肿瘤、子宫内膜异位症、特发性真性性早熟以及辅助生殖技术中广泛应用,本文对其在妇科的应用现状进行综述。     

A case of hypothalamic astrocytoma with precocious puberty]

A case of hypothalamic astrocytoma with precocious puberty is presented. In July 1989, a 2-year-old girl was admitted to our hospital because of vaginal bleeding and enlargement of breasts. Breast development was Tanner's stage 3 and no pubic hair was present. Endocrinological evaluation revealed a slightly high level of LH, but the responses of LH and FSH to LH-RH test resulted in exceedingly high values similar to those in adults. Plain CT scan showed an isodense mass in the suprasellar cistern which was not enhanced following administration of contrast medium. MR imaging revealed the precise location of the mass attached to the posterior hypothalamus between the pituitary stalk and the mamillary bodies in sagittal view. The signal intensity of the mass was homogenous and isointense relative to the gray matter on T1 weighted image. But on T2 weighted image, it showed high signal intensity compared with the normal brain parenchyma. A right fronto-temporal craniotomy was performed and the tumor was partially removed. Histological examination disclosed moderate hypercellularity of glial cells but no neurons were visible. This appeared to be astrocytoma grade II. In the literature, CT and MRI behaviour of hypothalamic hamartomas are almost similar to our case. Therefore we think it is not possible at the present time to differentiate a low grade astrocytoma from hamartoma when using CT and MRI alone. In this case, the mechanism of development of precocious puberty seemed to be due to hypothalamic compression by the tumor.     

Pubertas praecox and hypothalamic hamartoma

Summary Precocious puberty of cerebral origin is classified into pseudoprecocious puberty and true precocious puberty. Pseudoprecocious puberty is caused by HCG secreting tumours. True precocious puberty is caused by various hypothalamic diseases. Among them, hypothalamic hamartoma is the most common cause. Precocious puberty is caused by elevated blood pituitary gonadotropin concentration, secondary to the elevated hypothalamic LHRH secretion. The hypothalamic hamartoma is not infrequently associated with laughing (gelastic) seizures as well as convulsions. Diagnosis of a hypothalamic hamartoma is easily made by CT. Although the hypothalamic hamartoma is difficult to operate on, the value of surgery is stressed for treatment of precocious puberty. This is also confirmed by recent reports.     

Precocious puberty due to a hypothalamic hamartoma.

A case of precocious puberty due to a hypothalamic hamartoma is presented. Concentrations of plasma LH and FSH, testosterone and its derivatives were found to be elevated. Circadian rhythms of LH were also observed. After removal of the mass, plasma LH and FHS concentrations declined to nearly half the preoperative levels.     

Gonadotrophin-releasing hormone--diversity of functions and clinical applications

Gonadotrophin-releasing hormone (GnRH) plays a pivotal role in the regulation of the reproductive system. Chemically synthesised GnRH and analogues have found wide application in clinical medicine. Pulsatile administration of GnRH is used in the treatment of infertility and cryptorchidism. GnRH agonists inhibit gonadotrophin by pituitary desensitisation while antagonists compete out the effects of endogenous GnRH. These agents find application in contraception, the treatment of hormone-dependent neoplasms, precocious puberty, endometriosis, porphyria and disturbances of the menstrual cycle. It is now apparent that GnRH has been co-opted during evolution for functions other than the stimulation of gonadotrophins. GnRH has paracrine (local) effects in the gonads and placenta, acts as a neurotransmitter in the central nervous system, and has autocrine regulatory effects in some tumour cells. Evolutionary studies in non-mammalian vertebrates show that the GnRH gene has been duplicated to produce different molecular forms of unknown function. In addition to producing GnRH, the GnRH precursor is cleaved to produce peptides with novel activities, including prolactin inhibition.     

Hypothalamic hamartoma successfully treated by operation. Case report

An 18-month-old boy was diagnosed as having a hypothalamic hamartoma. When he was 1 year old, he developed precocious puberty, and at 18 months old, endocrinological tests revealed abnormally high follicle-stimulating hormone, luteinizing hormone, and testosterone levels. The center of the hamartoma was subtotally excised, as confirmed on the postoperative computerized tomography scan. Precocious puberty subsided after the operation.     

Controlling precocious puberty--surgical excision of hypothalamic hamartoma causing precocious puberty

Among the causes of precocious puberty, hypothalamic hamartoma comprises a small percentage. However, the frequency of precocious puberty in the presence of hypothalamic hamartoma is quite high. Recently, results of surgery in 14 cases of hypothalamic hamartoma were reported. Precocious puberty completely subsided in three cases and slight improvement was achieved in another three cases. We performed surgery in four patients with hypothalamic hamartomas, with the goal of decreasing the symptoms of precocious puberty. The patients were two females (aged 1 yr, 3 mo and 6 mo) and two males (aged 3 yr, 7 mo and 1 yr, 9 mo). The main symptoms were precocious puberty and mental retardation of varying degrees. The males had excessive growth of body and external genitalia, while the females had genital bleeding and premature breast development. In each case, computed tomographic scans disclosed a round, isodense mass in the interpeduncular cistern, attached to the base of the hypothalamus. Contrast enhancement was negative. Endocrinologically, in case 1, testosterone was 92.6 ng/ml, FSH was 16 mIU/ml, and LH was 2.2 mIU/ml. Although LH was within normal limits, it overresponded to LH-RH stimulation. In case 2, estrogen was 13.5 ng/day, LH was 5.2 mIU/ml, FSH was 5.3 mIU/ml, and LH showed an exaggerated response to LH-RH stimulation. In case 3, testosterone was 362 ng/ml, LH was 8.8 mIU/ml, FSH was 4.8 mIU/ml, and LH showed an abnormally high response to LH-RH stimulation. In case 4, LH was 18.4 mIU/ml, FSH was 12.0 mIU/ml, and both hormones were stimulated abnormally strongly by LH-RH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cervical sympathectomy inhibits axonal transport of gonadotropin-releasing hormone during continuous exposure to light in male rats

To examine the effects of cervical sympathectomy on the transport of gonadotropin-releasing hormone (GnRH) between the hypothalamic neurons and the median eminence, 16 male rats were assigned into four groups: control (C), light (L), light-sympathectomy (LS), and light-colchicine (LC). The C group was kept under a normal circadian rhythm for 2 weeks, and the L group was kept under continuous exposure to light for the same period. The LS group underwent bilateral cervical sympathectomy before being kept under continuous light conditions for 2 weeks. The LC group received colchicine into the cerebral ventricle after being kept under continuous light for 12 days; subsequently, this group was also housed for 2 days under continous light. After these procedures, blood was collected and serum luteinizing hormone (LH) levels were measured. All rats were perfused with a fixative, and GnRH neurons around the anterior commissure, as well as GnRH fibers and granules in the median eminence, were stained immunohistochemically. The L group showed a decreased number of GnRH neurons, increased concentrations of GnRH fibers and granules, and an increased LH level; however, in the LS and LC groups, these changes were not seen. The response in the LS group resembled that in the LC group. Considering the action of colchicine, which inhibits axonal transport, it is suggested that cervical sympathectomy also inhibits axonal transports of GnRH between the GnRH neurons and the median eminence during continuous exposure to light.     

奇士肽神经内分泌网络与生殖功能调控

十余年前奇士肽(Kisspeptin)的发现已成为人类生殖功能调控的新里程碑,更新了神经内分泌调控生殖功能的认识。奇士肽神经元联动兴奋性神经激肽B和抑制性强啡肽神经元形成KNDy网络,从上游调控GnRH的脉冲分泌和下丘脑-垂体-性腺轴功能。KNDy神经元应答性激素的负反馈和正反馈信号、介导青春期启动和在下丘脑神经内分泌网络反映身体能量代谢状态方面起关键性作用。     

Medical therapy of hypothalamic diseases

Summary Hormonal disturbances caused by hypothalamic pathology can be treated effectively by target hormone replacement in the case of failure of glandotropic hormone secretion. Hyposomatotropism in children has to be substituted by parenteral administration of growth hormone. In addition gonadotropins respectively gonadotropin releasing factor have to be given in order to restore fertility in hypothalamic hypogonadism. Posterior pituitary failure can be adequately replaced by administration of analogues of antidiuretic hormone.Hypothalamic pathology causing hypersecretion of anterior pituitary hormones may also be accessable to medical treatment. This pertains particularly to hyperprolactinemia and precocious puberty. However, there is no medical therapy so far for hypothalamic disturbances leading to veterative dysfunction like disturbances of temperature regulation and control of thirst and polyphagia. In this situation symptomatic correction of the abnormality represents the only possibility to keep these patients alive.     

Hypothalamic Suppression Decreases Bone Strength Before and After Puberty in a Rat Model

The incidence of menstrual irregularities, both primary and secondary amenorrhea, has been reported to be as high as 60%, with the highest incidence in younger athletes, suggesting possible adverse effects on bone development. It was hypothesized that in a rat model, suppressed hypothalamic activity via a gonadotropin-releasing hormone antagonist (GnRH-a) before onset of puberty would result in a relatively larger bone strength deficit compared with suppression after puberty. Hypothalamic suppression was achieved by providing GnRH injections. Animals received injections for 25 days either before puberty (pre group) (age 23–46 days) or after puberty (post group) (age 65–90 days). Body weights and uterine weights were measured. Serum estradiol was assayed. Mechanical strength of the right femora and histomorphometry of the left femur were measured. Suppression of the hypothalamic–pituitary–gonadal axis was confirmed by significant atrophy of uterine tissue and suppressed estradiol levels. The peak moment was significantly lower in the pre and post GnRH-a groups compared with control. The percentage difference of the average peak moment and stiffness values from the respective age-matched control groups yielded a greater percentage difference in the pre group. The cortical area was less in the GnRH-a-treated groups, but no significant difference between the relative deficits between pre and post groups were found. Hypothalimic–pituitary–gonadal axis suppression before puberty resulted in a significantly larger deficit in mechanical strength compared with postpubertal animals. The time before puberty may represent a time when skeletal strength is more compromised. Women experience both primary and secondary amenorrhea; however, the treatment may need to be different for each condition.     

Primary intracranial germ cell tumor in the right basal ganglia and its vicinity area--a report of the case with germinoma and choriocarcinoma histologically

A case of intracranial germ cell tumor in the right basal ganglia and it's vicinity area was presented and previous reported cases were reviewed. The patient was a 11-year-old boy with precocious puberty. His illness started with left hemiparesis and mental disturbance, i.e. behavioral and emotional change one year prior to admission. Enhanced CT demonstrated a round lesion of high density, with relatively low density in the center portion. The tumor developed from the right putamen to thalamus, and involved toward hypothalamic region on coronary CT. Hormonal studies revealed abnormal levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), human chronic gonadotropin (HCG), and testosterone. In addition to excessively high levels of HCG in the urine, serum and CSF, high elevation of plasma LH and low of plasma FSH were revealed. On 3 June 1980, right temporal craniotomy was performed and a piece of the tumor was removed. Tumor's tissue was diagnosed as germinoma by pathohistological examination. As the effect of postoperative Co-60 radiation, high density area on CT disappeared and remained as well margined low density area. On repeated CTs and HCG-measurements on further, recurrent sign was not noted up to now. However, as a result of pathohistological studies in details, syncytiotrophoblast generally seen in the choriocarcinoma seem to be presented in it's tissue. Therefore, by means of peroxidase labeled antibody method, the authors proved HCG in syncytial cells of the tumor's tissue. There are very little reports on quantification of HCG in primary intracranial germ cell tumor with precocious puberty. Serial measurements of HCG are useful for following the diagnosis and therapy of primary intracranial germ cell tumors. In this report, the authors provide evidence that the syncytial cell mixed in intracranial germinoma secrets HCG.     

The relationship between magnetic resonance imaging findings and clinical manifestations of hypothalamic hamartoma.

OBJECT: Hypothalamic hamartoma is generally diagnosed based on its magnetic resonance (MR) imaging characteristics and the patient's clinical symptoms, but the relationship between the neuroradiological findings and clinical presentation has never been fully investigated. In this retrospective study the authors sought to determine this relationship. METHODS: The authors classified 11 cases of hypothalamic hamartoma into two categories based on the MR findings. Seven cases were the "parahypothalamic type," in which the hamartoma is only attached to the floor of the third ventricle or suspended from the floor by a peduncle. Four cases were the "intrahypothalamic type," in which the hamartoma involved or was enveloped by the hypothalamus and the tumor distorted the third ventricle. Six patients with the parahypothalamic type exhibited precocious puberty, which was controlled by a luteinizing hormone-releasing hormone analog, and one patient was asymptomatic. No seizures or mental retardation were observed in this group. All patients with the intrahypothalamic type had medically intractable seizures, and precocious puberty was seen in one. Severe mental retardation and behavioral disorders including aggressiveness were seen in two patients. The seizures were controlled in only one patient, in whom stereotactically targeted irradiation of the lesion was performed. This topology/symptom relationship was reconfirmed in a review of 61 reported cases of hamartoma, in which the MR findings were clearly described. The parahypothalamic type is generally associated with precocious puberty but is unaccompanied by seizures or developmental delay, whereas the intrahypothalamic type is generally associated with seizures. Two thirds of patients with the latter experience developmental delays, and half also exhibit precocious puberty. CONCLUSIONS: Classification of hypothalamic hamartomas into these two categories based on MR findings resulted in a clear correlation between symptoms and the subsequent clinical course.     

Age-related decrease in hypothalamic gonadotropin-releasing hormone (GnRH) gene expression, but not pituitary responsiveness to GnRH, in the male Brown Norway rat

As is the case in humans, aging male Brown Norway (BN) rats exhibit both primary and secondary (hypothalamic/pituitary) testicular failure. We hypothesized that secondary testicular failure in aging BN rats is due to alterations in both hypothalamic and pituitary function. In order to determine whether gonadotropin-releasing hormone (GnRH) gene expression is altered with aging, we compared hypothalamic preproGnRH (ppGnRH) mRNA by in situ hybridization histochemistry and GnRH peptide content in microdissected brain areas by radioimmunoassay in intact (or sham-operated) young, middle-aged, and old male rats. In addition, we determined hypothalamic-pituitary responsiveness to the removal of testicular feedback by comparing ppGnRH messenger RNA (mRNA) and gonadotropin levels in sham-operated and orchidectomized young, middle-aged, and old rats. In sham-operated rats, both the cellular ppGnRH mRNA content and the number of neurons expressing ppGnRH mRNA were lower in old compared with young and middle-aged rats. In addition, GnRH content decreased with aging in intact rats in 2 of the 3 brain areas examined, and GnRH content tended to decrease with aging in the third region. Morning serum luteinizing hormone (LH) levels were unchanged with aging, whereas follicle-stimulating hormone (FSH) was significantly increased in old compared with younger intact rats. The cellular ppGnRH mRNA content also decreased with aging in orchidectomized rats, although the number of neurons expressing ppGnRH mRNA was unchanged with aging in these rats. Within age groups, the cellular ppGnRH mRNA content was higher in orchidectomized than in sham-operated rats, though there was no effect on the number of neurons expressing GnRH. In a second study, we compared pituitary responsiveness to GnRH by measuring serum LH and FSH levels after GnRH administration in intact BN rats of different ages. The LH response to GnRH was unchanged with aging, whereas the FSH response to GnRH tended to increase with aging. Despite similar LH responses, the testosterone (T) response to GnRH declined progressively with aging. A third study assessed age-related changes in the circadian rhythm of circulating LH, T, and corticosterone (B) levels. LH levels over a 24-hour period decreased with aging and tended to be lower in the morning hours in all age groups, and circadian rhythmicity was blunted in middle-aged and old compared with young rats. T levels over 24 hours declined progressively with aging, and these levels showed a bimodal diurnal variation in young rats, a variation that was not evident in older animals. B levels over a 24-hour period were lower in old than in younger animals, and with aging, there was dampening of the amplitude of the circadian rhythm of B. Taken together, these findings suggest that secondary testicular failure in aging male BN rats is due in part to decreased GnRH gene expression rather than to decreased pituitary responsiveness to GnRH. This reduction in GnRH gene expression with aging is not dependent on testicular feedback factors. Finally, the blunted circadian rhythmicity of LH and T secretion with aging provides further evidence of altered hypothalamic regulation of gonadal hormone secretion in old animals.